To evaluate the safety and long-term efficacy of computed tomography-guided percutaneous ethanol ablation for benign primary and secondary hyperfunctioning adrenal disorders.
We retrospectively ...evaluated the long-term results of nine patients treated with computed tomography-guided percutaneous ethanol ablation: eight subjects who presented with primary adrenal disorders, such as pheochromocytoma, primary macronodular adrenal hyperplasia and aldosterone-producing adenoma, and one subject with Cushing disease refractory to conventional treatment. Eleven sessions were performed for the nine patients. The patient data were reviewed for the clinical outcome and procedure-related complications over ten years.
Patients with aldosterone-producing adenoma had clinical improvement: symptoms recurred in one case 96 months after ethanol ablation, and the other patient was still in remission 110 months later. All patients with pheochromocytoma had clinical improvement but were eventually submitted to surgery for complete remission. No significant clinical improvement was seen in patients with hypercortisolism due to primary macronodular adrenal hyperplasia or Cushing disease. Major complications were seen in five of the eleven procedures and included cardiovascular instability and myocardial infarction. Minor complications attributed to sedation were seen in two patients.
Computed tomography-guided ethanol ablation does not appear to be suitable for the long-term treatment of hyperfunctioning adrenal disorders and is not without risks.
Starting from Windows 11, the Trusted Platform Module (TPM) 2.0 has become a computer requirement, providing hardware-based security capabilities. This poses a challenge to digital forensics experts, ...as the number of BitLocker-encrypted evidence protected by TPM tends to increase. This paper presents a forensic method for obtaining the BitLocker Volume Master Key (VMK) from TPM-protected evidence using Intel DCI technology and reverse engineering techniques. It shows how to enable Intel DCI in the firmware, reverse the Windows Boot Manager UEFI application, and debug the target computer using a USB 3 A–A cable to retrieve the VMK from memory. We have effectively applied the presented method on a computer with a 7th-generation Intel processor containing a BitLocker-encrypted volume with TPM protection and Windows 11 Pro. As a result, we were able to fully decrypt the BitLocker volume with the VMK and gain data access. We consider, however, that the success of the presented method depends on the ability to enable Intel DCI in the target computer, which may not be feasible in every system.
Aiming to verify the movements of the bottlenose dolphin (Tursiops truncatus) at Rio de Janeiro State coast, southeastern Brazil, we performed a photoidentification comparison between the catalogued ...individuals of the Cagarras Archipelago (23° 02' S and 43° 12' W) in 2004 and 2006 (n = 26) and the images obtained (n = 179) during the Southeastern Cetaceans Expedition, conducted during months of June and November of 2005. Eight individuals (three females and five dolphins of unknown gender) identified in the Cagarras Archipelago were resighted in the Grande Island (23° 21'S and 44° 15' W), about 100 km southwestwards from Cagarras Archipelago. The observed movements include distances commonly recorded for the species elsewhere and are probably related to search for prey.
Recent evidence suggests that generation of neutrophil extracellular traps (NETosis), one of the components of immunothrombosis, is associated with the pathogenesis of both venous thromboembolism and ...sickle cell disease (SCD). NETosis is a complex process regulated by several proteins such as peptidyl arginine deaminase 4 (PADI4), neutrophil elastase (ELANE), and myeloperoxidase (MPO). Among these regulators, PADI4 is responsible of histone citrullination, an essential step for NETosis. Accordingly, its inhibition has been recently cited as a promising therapeutic strategy for diseases such as SCD. Although attractive, this strategy requires supportive evidence of its role in the pathogenesis of SCD.
Patients from two independent cohorts were enrolled in this study. Samples were obtained at steady state (53 patients) or during acute episodes of vaso‐occlusive crisis (VOC; 28 patients) in patients from cohort 1. mRNA was extracted from granulocytes to analyze PADI4, ELANE, and MPO expression by qPCR. Furthermore, plasma activity of PADI4 was assessed from an independent cohort in 15 patients, within 24 hours from admission for VOC. Race‐matched healthy individuals from the same geographic regions were used as controls for each cohort.
Higher levels of gene expression of PADI4 and ELANE were observed during VOC. Furthermore, plasma activity of PADI4 was higher in acute VOC when compared to healthy individuals. These results demonstrate that NETosis regulators are modulated during acute VOC, and pave the way for studies of PADI4 inhibition as a therapeutic strategy for acute VOC in SCD.
Brazil has the second-largest dairy cattle herd in the world, and bovine mastitis still can cause significant losses for dairy farmers. Despite this fact, little information is available about milk ...microbial composition of Brazilian dairy cows, as well as the potential use of bacteriophages in the control of S. aureus. Here, we investigated milk bacterial composition of 28 Holstein Fresian cows (109 teats), selected in the dry-off period, using 16S rRNA analysis. Furthermore, a representative S. aureus strain (UFV2030RH1) was obtained at drying-off for isolation of a bacteriophage (vB_SauM-UFV_DC4, UFV_DC4) and bacterial genomic comparison purposes. Our outcomes revealed that Staphylococcus was the third most prevalent genus and positively correlated with subclinical mastitis events. As a major finding, genomic analyses showed the presence of adhesive matrix molecules that recognize microbial surface components (MSCRAMM) in UFV2030RH1 and might indicate great biofilm formation capability. A minimum inhibitory concentration (MIC) assay showed that resistance to ampicillin was the highest among the antibiotic tested in S. aureus 3059 and UFV2030RH1, displaying values four and sixteen times greater than MIC resistance breakpoint, respectively. Together, our results suggest that Staphylococcus is highly prevalent in dairy cows at drying-off and the use of the phage UFV_DC4 as a biocontrol agent must be investigated in future studies.
Latin America and Caribbean (LAC) is a developing region characterized for its importance for global food security, producing 23 and 11% of the global beef and milk production, respectively. The ...region's ruminant livestock sector however, is under scrutiny on environmental grounds due to its large contribution to enteric methane (CH4) emissions and influence on global climate change. Thus, the identification of effective CH4 mitigation strategies which do not compromise animal performance is urgently needed, especially in context of the Sustainable Development Goals (SDG) defined in the Paris Agreement of the United Nations. Therefore, the objectives of the current study were to: 1) collate a database of individual sheep, beef and dairy cattle records from enteric CH4 emission studies conducted in the LAC region, and 2) perform a meta-analysis to identify feasible enteric CH4 mitigation strategies, which do not compromise animal performance. After outlier's removal, 2745 animal records (65% of the original data) from 103 studies were retained (from 2011 to 2021) in the LAC database. Potential mitigation strategies were classified into three main categories (i.e., animal breeding, dietary, and rumen manipulation) and up to three subcategories, totaling 34 evaluated strategies. A random effects model weighted by inverse variance was used (Comprehensive Meta-Analysis V3.3.070). Six strategies decreased at least one enteric CH4 metric and simultaneously increased milk yield (MY; dairy cattle) or average daily gain (ADG; beef cattle and sheep). The breed composition F1 Holstein × Gyr decreased CH4 emission per MY (CH4IMilk) while increasing MY by 99%. Adequate strategies of grazing management under continuous and rotational stocking decreased CH4 emission per ADG (CH4IGain) by 22 and 35%, while increasing ADG by 22 and 71%, respectively. Increased dietary protein concentration, and increased concentrate level through cottonseed meal inclusion, decreased CH4IMilk and CH4IGain by 10 and 20% and increased MY and ADG by 12 and 31%, respectively. Lastly, increased feeding level decreased CH4IGain by 37%, while increasing ADG by 171%. The identified effective mitigation strategies can be adopted by livestock producers according to their specific needs and aid LAC countries in achieving SDG as defined in the Paris Agreement.
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•The Latin America and Caribbean (LAC) cattle livestock encompasses 28% of global herd.•Thirty-four potential enteric methane (CH4) mitigation strategies were evaluated.•Six strategies decreased CH4 emission while increased animal productivity.•They can be adopted by livestock producers according to their specific needs.•And promptly aid LAC countries in achieving SDG as defined in the Paris Agreement.
To investigate whether allopurinol exerts a protective effect on kidneys by measuring new kidney injury biomarkers (NGALp, NGALu, KIM 1 and IL 18) and analysing the renal function and histology in ...uninephrectomised rats subjected to ischaemia-reperfusion injury.
Thirty two Wistar rats were randomly allocated to four groups: Sham (S): laparotomy; Control (C): laparotomy and ischaemia-reperfusion in the left kidney; Control Allopurinol (CA): laparotomy and allopurinol at a dose of 100mg·kg 1·d 1; and Allopurinol (A): laparotomy ischaemia-reperfusion in the left kidney and allopurinol at a dose of 100mg·kg 1·d 1. The NGALp, NGALu, KIM 1, IL 18 and creatinine levels and the kidney histology were analysed. The significance level was established as p<0.05.
Creatinine level increased in all the groups, with A ≈ C > S ≈ CA. The NGALp, NGALu and IL 18 levels exhibited similar behaviour in all the groups. KIM 1 was higher in group A than C and showed intermediate values in groups S and CA. Severity of injury in the left kidney was greater in groups C and A compared to S and CA.
Allopurinol did not exert protective or damaging effects on the kidneys of rats subjected to ischaemia-reperfusion injury.
Introduction: Recent evidence suggests that coagulation activation is involved in the pathogenesis of progressive organ failure in Sickle Cell Anemia (SCA). In addition, generation of neutrophil ...extracellular traps (NETosis), one of the components of immunothrombosis, has been associated with the pathogenesis of both venous thromboembolism and SCA. NETosis is a complex process that involves the orchestrated participation of several proteins such as peptidyl arginine deaminase (PADI4), neutrophil elastase (ELANE) and myeloperoxidase (MPO). PADI4 mediates histone citrulination, an essential step for NETosis. Accordingly, its inhibition has been recently cited as a potential therapeutic strategy for diseases in which NETosis are thought to play a relevant pathogenic role such as SCA. Although attractive, investment in PADI4 inhibitors in SCA requires gathering of more convincing evidences of the role of this enzyme in its pathogenesis. Herein, we used two cohorts of patients to investigate the expression of NETosis regulators (PADI4, ELANE and MPO) in SCA at steady state and during acute crisis, and to assess whether PADI4 activity is increased in any of these states. Methods: patients were recruited from two different centers in Brazil. Whole blood samples were obtained from patients from cohort 1 at steady state or during acute crisis (within 24 hours from admission). mRNA was obtained from granulocytes isolated by Ficoll gradient and gene expression of PADI4, ELANE, and MPO were measured by qPCR. In patients from cohort 2, PADI4 and MPO activity were measured in samples obtained within 24 hours from admission and after patient discharge (convalescence) using commercial kits in serum (MPO, Myeloperoxidase activity assay kit; ab105136) and plasma (PADI4, PAD4 Inhibitor Screening Assay Kit; Cayman chemical). Healthy individuals from the same geographic region were used as controls for each cohort, independently Results: In total, 54 steady state patients, 27 acute crisis and 40 healthy volunteers were evaluated for mRNA expression of NETosis regulators. Patients in acute crisis expressed higher levels of PADI4, MPO and ELANE compared to both healthy volunteers and patients in steady-state. Furthermore, plasma activity of PADI4 was higher in acute crisis when compared to healthy individuals (7.36x106 vs 5.24x106; P= 0.002), with no decrease after discharge (median of 13.5 days after admission) (7.36x106vs 7.41x106; P= 0.004). No differences were observed in serum MPO activity during acute crisis. Conclusion: we demonstrate that the mRNA expression of NETosis regulators, including PADI4, is increased in SCA; and that this increase is associated with higher levels of PADI4 activity in plasma during acute crisis. These results support the concept of PADI4 inhibition as a therapeutic strategy for acute episodes of SCA, and warrant additional studies in this area.
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No relevant conflicts of interest to declare.
► UPLC–APCI-MS method to quantify chlorpromazine in human plasma. ► Method was applied in a relative bioavailability study in order to compare a test chlorpromazine 100
mg simple dose formulation. ► ...The chlorpromazine was extracted from human plasma by a simple liquid–liquid extraction. ► This method agrees with the requirements proposed by the US Food and Drug Administration of high sensitivity, specificity and high sample throughput in comparative pharmacokinetic assays such as bioequivalence.
In the present study a method to quantify chlorpromazine in human plasma using cyclobenzaprine as the internal standard (IS) is described. The analyte and the IS were extracted from human plasma by a liquid–liquid extraction with diethyl ether/dichloromethane (70/30, v/v) and analyzed by an ultra performance liquid chromatography (UPLC) coupled to an electrospray tandem triple quadrupole mass spectrometer in positive mode (UPLC–ES
+-MS/MS). Chromatography was performed isocratically on an Aquity UPLC BEH C18 1.7
μm (50
mm
×
2.1
mm i.d.) operating at 40
°C. The mobile phase was a mixture of 65% water
+
1% formic acid and 35% of acetonitrile at a flow-rate of 0.5
mL/min. The lowest concentration quantified was 0.5
ng/mL and a linear calibration curve over the range 0.5–200
ng/mL was obtained, showing intra-assay precisions from 2.4 to 5.8%, and inter-assay precisions from 3.6 to 9.9%. The intra-assay accuracies ranged from 96.9 to 102.5%, while the inter-assay accuracies ranged from 94.1 to 100.3%. This analytical method was applied in a relative bioavailability study in order to compare a test chlorpromazine 100
mg simple dose formulation versus a reference in 57 volunteers of both sexes. The study was conducted in an open randomized two-period crossover design and with a fourteen days washout period. Plasma samples were obtained over a 144-h interval. Since the 90% CI for both
C
max, AUC
last and AUC
0–inf were within the 80–125% interval proposed by the Food and Drug Administration and ANVISA, it was concluded that chlorpromazine 100
mg/dose was bioequivalent to the reference formulation, according to both the rate and extent of absorption.
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